вход по аккаунту


Fenofibrate inhibits reactive amyloidosis in mice.

код для вставкиСкачать
Vol. 46, No. 6, June 2002, pp 1683–1688
DOI 10.1002/art.10327
© 2002, American College of Rheumatology
Fenofibrate Inhibits Reactive Amyloidosis in Mice
Takehiro Murai,1 Toshiyuki Yamada,2 Takashi Miida,1 Katsumitsu Arai,1 Naoto Endo,1
and Tadamasa Hanyu1
(4,5). SAA, an acute-phase reactant, is synthesized predominantly in the liver after stimulation by
inflammation-related cytokines, such as interleukin-1
(IL-1), IL-6, and tumor necrosis factor ␣ (TNF␣) (6).
Although SAA is insoluble by itself, it circulates in the
blood as an apolipoprotein of high-density lipoprotein
(HDL). When SAA is dissociated from HDL and partially degraded, it is deposited as AA amyloid fibrils in
the extracellular space of vital tissues (5,7), leading to
renal failure and gastrointestinal tract dysfunction (8).
Prolonged hyperproduction of SAA with chronic inflammation is the primary cause of reactive amyloidosis,
although other factors, such as genetic background (8,9)
and impaired processing of SAA (5,10), may contribute
to amyloidogenesis.
Fibrate derivatives, such as bezafibrate and fenofibrate, have been used to treat hypertriglyceridemia or
combined hyperlipidemia. Their main effect is to reduce
levels of triglycerides rather than cholesterol (11,12).
Recent studies have revealed that fibrates regulate not
only lipid metabolism, but also inflammation (13). Fibrates were shown to decrease plasma concentrations of
inflammatory cytokines, such as IL-6, TNF␣, and
interferon-␥, as well as concentrations of fibrinogen and
C-reactive protein, in patients with atherosclerosis
In this study, we examined whether fenofibrate
would inhibit AA amyloidosis by reducing SAA levels in
a mouse model. We quantitated the amyloid deposits
and SAA concentrations in mice with and without
Objective. To examine the effects of the lipidlowering agent fenofibrate on experimental AA amyloidosis and on serum amyloid A (SAA) levels.
Methods. Fenofibrate was administered orally in
a mouse model of amyloidosis, which is induced by
injections of amyloid-enhancing factor and Freund’s
complete adjuvant. Fenofibrate was given for 3 weeks,
including a 1-week course before induction of amyloidosis. Splenic amyloid deposits were evaluated histologically, and SAA levels were measured.
Results. Fenofibrate inhibited the formation of
splenic amyloid deposits and suppressed the elevation
of SAA levels.
Conclusion. Fenofibrate inhibits experimental
amyloidosis by reducing levels of the precursor SAA.
Reactive AA amyloidosis is a complication of
chronic inflammatory disease which compromises quality of life and worsens the long-term prognosis. In an
autopsy study in Japan, rheumatoid arthritis (RA) was
present in 61.4% of subjects with reactive amyloidosis,
and 25.2% of subjects with RA had this complication.
Moreover, reactive amyloidosis was the cause of death in
12.5% of RA patients (1). In studies of gastrointestinal
tract and renal biopsy samples, amyloid deposits were
present in 13.3% and 19%, respectively, of RA patients
Reactive amyloidosis is caused by deposits of
insoluble fibrils consisting of AA amyloid protein, which
is derived from its precursor, serum amyloid A (SAA)
Supported by grant-in-aid 13671496 for scientific research
from the Japan Society for the Promotion of Science.
Takehiro Murai, MD, Takashi Miida, MD, Katsumitsu Arai,
MD, Naoto Endo, MD, Tadamasa Hanyu, MD: Niigata University
School of Medicine, Niigata, Japan; 2Toshiyuki Yamada, MD: Juntendo University School of Medicine, Tokyo, Japan.
Address correspondence and reprint requests to Takashi
Miida, MD, Department of Laboratory Medicine, Niigata University
School of Medicine, Asahimachi 1-757, Niigata 951-8510, Japan.
E-mail: [email protected]
Submitted for publication June 12, 2001; accepted in revised
form February 21, 2002.
Agents. Fenofibrate and fenofibric acid (FA) in bulk
were kindly provided by Fournier Laboratories (Dijon,
France). FA is the active metabolite of fenofibrate and its
major form in the circulation.
Animals. A total of 60 female CBA/Jn mice (age 8
weeks, weight 20–24 gm) were purchased from Charles River
Japan (Kanagawa, Japan) and maintained under specific
pathogen–free conditions in our animal facility. We housed 5
mice per cage and fed them with regular chow and water ad
libitum for 1 week to stabilize their metabolic condition. Thus,
9-week-old mice were used in our experiments.
Preparation of fenofibrate-containing diet. Regular
mice chow pellets were ground into powder using a food
processor and uniformly mixed with fenofibrate to create
0.05%, 0.1%, and 0.2% mixtures (weight/weight). We added
sterile distilled water to the individual mixture to form small
pellets, which were allowed to dry completely at room temperature. Since each mouse consumed 3.0–3.5 gm of chow/day,
dosages of 0.05%, 0.1%, and 0.2% fenofibrate corresponded to
75, 150, and 300 mg of fenofibrate/kg/day. These concentrations of fenofibrate were determined by previous experiments
using rodents (16,17).
Preparation for amyloid induction. Amyloidenhancing factor (AEF) and Freund’s complete adjuvant
(CFA) were used for induction of experimental AA amyloidosis. AEF can dramatically shorten the lag phase of amyloid
deposition in mice. Its chemical nature has not been clearly
identified, but microfibrils or fibril-forming peptides in the
preparation are believed to serve as a nidus for further amyloid
formation (18). AEF was prepared as glycerol extracts of
spleen from amyloidotic animals as previously described (19).
CFA was purchased from Difco (Detroit, MI).
Protocol. Mice were divided into 2 groups, AEF/
CFA⫺ and AEF/CFA⫹, depending on whether amyloidosis
was induced. These 2 groups were subdivided, based on the
dosage of fenofibrate, into 2 (0% and 0.2% fenofibrate) and 4
(0%, 0.05%, 0.1%, and 0.2% fenofibrate) subgroups, respectively. Each subgroup contained 10 mice.
Amyloidosis was induced as follows: on day 0, AEF
(0.2 ml) was injected intraperitoneally. On day 1, a single
intraperitoneal injection of CFA (0.5 ml) was given. No further
injections were needed. Mice were fed the indicated
fenofibrate-containing diet or regular chow for 3 weeks (from
day ⫺7 to day 14). To confirm that the doses of fenofibrate
were consistent, the food intake of mice in each cage was
recorded daily. All mice were bled from the retroorbital
venous plexus under anesthesia on days ⫺7, 0, 2, and 7. On day
14 (the end of the experiments), all mice were killed, and the
final blood samples were obtained by cardiac puncture. Serum
was isolated by centrifugation and stored at ⫺80°C until
assayed. Livers and spleens were also collected for histologic
Measurement of FA concentration. FA concentrations
in plasma obtained on day 14 were measured by highperformance liquid chromatography (HPLC). First, either the
internal standard (flurbiprofen; Kaken Pharmaceutical, Tokyo,
Japan) or the FA standard was added to each plasma sample.
Second, the sample containing the internal standard was
treated with 0.5M HCl/n-hexane/ethyl acetate (1/9/1 volume/
volume/volume). The organic phase was mixed with 0.1M
Na2HPO4. Then, the liquid phase was treated with 0.5M
HCl/n-hexane/ethyl acetate (1/19/1 v/v/v). The organic phase
was dried down and dissolved in methanol solution. Finally, the
extract was separated by HPLC (LC-10A system and a C-R7A
plus data processor; Shimadzu, Kyoto, Japan) using an analytical column (CapCell Pak C18 SG120, 150 ⫻ 4.6–mm inner
diameter; Shiseido, Tokyo, Japan) at 35°C with ultraviolet
detection (254 nm). The mobile phase consisted of a mixture of
0.02M sodium citrate buffer (pH 3.7)/acetonitrile (6/4 v/v). The
Figure 1. Plasma fenofibric acid (FA) concentration on day 14. The
FA level correlated positively with the dose of fenofibrate in the study
diet. Values are the mean and SEM. AEF ⫽ amyloid-enhancing factor;
CFA ⫽ Freund’s complete adjuvant; ND ⫽ not detectable.
plasma FA concentration was calculated from the peak area
ratio of FA to the internal standard.
Evaluation of amyloid deposits. After fixing the liver
and spleen in 10% buffered formaldehyde, we made paraffinembedded sections and stained them with hematoxylin and
eosin (H&E) and Congo red. Each splenic section was evaluated histologically for the severity of amyloid deposition, as
follows: 0 ⫽ no detectable amyloid, 1 ⫽ mild amyloid deposits
mainly in the perifollicular zone, 2 ⫽ moderate deposits, 3 ⫽
abundant deposits but an intact follicular structure, and 4 ⫽
severe deposits with destruction of the follicular structure.
Measurement of SAA, IL-6, and triglycerides in
plasma. SAA concentrations were measured in plasma samples on days –7, 0, 2, 7, and 14 by an enzyme-linked immunosorbent assay (ELISA) as previously described (5). IL-6 and
triglyceride concentrations were measured in plasma samples
on day 14 by ELISA (Endogen, Woburn, MA) and by an
enzymatic method (L-type Wako TG-H; Wako, Osaka, Japan),
Statistical analysis. All data are expressed as the mean
and SEM. The Mann-Whitney rank sum test was used to
determine the level of significance between group means. P
values less than 0.05 were considered significant.
FA concentration. On day 14, the plasma FA
level correlated positively with the dose of fenofibrate in
the study diet (Figure 1). In addition, the FA levels in
mice receiving 0.2% fenofibrate were similar in the
AEF/CFA⫺ and AEF/CFA⫹ groups.
General findings. Fenofibrate markedly inhibited
the macroscopic inflammatory response induced by
AEF/CFA injection. Although ascites and intraperitoneal adhesions were always seen in the AEF/CFA⫹
Figure 2. Hematoxylin and eosin–stained sections of spleen from mice with induced amyloidosis that were fed regular chow containing either (0%
fenofibrate (A), 0.05% fenofibrate (B), or 0.2% fenofibrate (C). The amyloid deposits in these sections correspond to severity grades 4, 2, and 0,
respectively (see Materials and Methods). (Original magnification ⫻ 100.)
groups, fenofibrate clearly suppressed the severity of the
inflammatory response. On H&E-stained sections, peroxisome formation was not observed in the liver in any
Amyloid examination. Histologic examination
showed that fenofibrate markedly prevented the formation of amyloid deposits in the spleen. In the AEF/
CFA⫺ group, there were no amyloid deposits in any
mice (data not shown). In the AEF/CFA⫹ group, we
found abundant amyloid deposits and severe destruction
of the follicular structure in mice receiving 0% fenofibrate (Figure 2A). In contrast, there were far fewer
amyloid deposits in fenofibrate-treated mice (Figures 2B
and C). The average severity score for amyloid deposition was highest in mice that received 0% fenofibrate
and lowest in mice that received 0.2% fenofibrate (Table
1). This inhibitory effect on amyloid deposition was
apparently dependent on the fenofibrate dose.
Changes in SAA concentration. Fenofibrate also
inhibited the elevation of SAA levels in mice after
AEF/CFA injections. In the AEF/CFA⫺ group, there
was no change in the SAA concentration during the
entire experiment in any mouse (data not shown). In the
AEF/CFA⫹ group, SAA concentrations gradually increased after injection (Figure 3). However, this AEF/
CFA-induced increase in SAA concentration was suppressed in a dose-dependent manner in mice that
received 0.05%, 0.1%, and 0.2% fenofibrate compared
with those that received 0% fenofibrate.
Plasma IL-6 and triglyceride concentrations. The
IL-6 level on day 14 was markedly higher in the AEF/
CFA⫹ group than in the AEF/CFA⫺ group
Table 1.
Histologic evaluation of amyloid deposits in the spleen of
dose (n)
0% (10)
0.2% (8)
0% (10)
0.05% (9)
0.1% (10)
0.2% (10)
Severity score†
Mean ⫾ SEM
severity score
3.2 ⫾ 0.1
2.2 ⫾ 0.2‡
1.4 ⫾ 0.3‡
0.5 ⫾ 0.2§
* AEF ⫽ amyloid-enhancing factor; CFA ⫽ Freund’s complete adjuvant.
† Values are the number of mice with the severity score (0 ⫽ no
detectable amyloid, 1 ⫽ mild amyloid deposits mainly in the perifollicular zone, 2 ⫽ moderate deposits, 3 ⫽ abundant deposits but an
intact follicular structure, 4 ⫽ severe deposits with destruction of the
follicular structure).
‡ P ⬍ 0.005 versus mice that received 0% fenofibrate in the same
§ P ⬍ 0.0001 versus mice that received 0% fenofibrate in the same
Table 3.
Effect of fenofibrate on plasma triglyceride concentrations*
Group, fenofibrate dose (n)
0% (10)
0.2% (8)
0% (10)
0.05% (9)
0.1% (10)
0.2% (10)
Triglycerides, mg/dl
114 ⫾ 27
13 ⫾ 2†
46 ⫾ 5
20 ⫾ 3‡
14 ⫾ 2†
16 ⫾ 1†
* Values are the mean ⫾ SEM (see Table 1 for definitions).
† P ⬍ 0.0005 versus mice that received 0% fenofibrate in the same
‡ P ⬍ 0.001 versus mice that received 0% fenofibrate in the same
Figure 3. Effect of treatment with fenofibrate on serum amyloid A
(SAA) concentrations before and after induction of amyloidosis. All
mice were fed regular chow or chow containing fenofibrate for 3 weeks
(day ⫺7 to day 14). Injections of amyloid-enhancing factor (AEF) and
Freund’s complete adjuvant (CFA) were given on day 0 and day 1,
respectively. Blood samples were obtained at the indicated intervals
from each mouse. Values are the mean ⫾ SEM. ⴱ ⫽ P ⬍ 0.05, ⴱⴱ ⫽
P ⬍ 0.005, and ⴱⴱⴱ ⫽ P ⬍ 0.0005 versus mice that received 0%
(Table 2). Among subgroups of the AEF/CFA⫹ group,
the mean IL-6 level was lowest in mice that received
0.2% fenofibrate. However, there was remarkable individual variation in IL-6 levels in the same subgroup.
Thus, we failed to show a significant correlation between the dose of fenofibrate and the plasma IL-6 level or
between the plasma IL-6 level and the SAA concentration.
Fenofibrate decreased plasma triglyceride levels
on day 14 in both the AEF/CFA⫺ and AEF/CFA⫹
groups. In the AEF/CFA⫺ group, the triglyceride concentration was 89% lower in mice that received 0.2%
fenofibrate than in those that received 0% fenofibrate
(Table 3). In the AEF/CFA⫹ group, the triglyceride
concentration was 57–70% lower in the fenofibratetreated mice than in those that received 0% fenofibrate.
Unlike reductions in amyloid deposits or SAA concenTable 2. Plasma interleukin-6 (IL-6) concentrations on day 14*
Group, fenofibrate dose (n)
0% (7)
0.2% (7)
0% (7)
0.05% (7)
0.1% (7)
0.2% (7)
IL-6, pg/dl
17 ⫾ 2
19 ⫾ 2
2,375 ⫾ 4,099
1,764 ⫾ 2,581
3,297 ⫾ 2,615
1,146 ⫾ 1,776
* Values are the mean ⫾ SEM (see Table 1 for other definitions).
trations, the reduction in triglyceride concentrations
almost reached the plateau in the mice that received
0.05% fenofibrate, the minimum dose in this
This study demonstrates that fenofibrate inhibits
reactive AA amyloidosis by reducing SAA in an inflammatory murine model. Histologic examination clearly
showed that fenofibrate suppressed amyloid deposits in
the spleen in the AEF/CFA⫹ group (Figure 2). The
higher the dose of fenofibrate, the lower the severity
score of amyloid deposits in the spleen (Table 1).
Corresponding to the severity of the amyloid deposits,
fenofibrate dose-dependently suppressed the elevated
SAA concentrations induced by inflammatory stimuli.
Furthermore, fenofibrate decreased macroscopic inflammatory responses such as massive ascites and intraperitoneal adhesions.
Although fenofibrate has been widely used in
Europe since 1975, its mechanism of action has only
recently been elucidated in detail. In 1990, peroxisome
proliferator–activated receptor ␣ (PPAR␣) was found to
be a ligand-dependent transcription factor (20). Fibrates
are ligands for this receptor, and beneficial effects of
fenofibrate on lipid metabolism are exerted via PPAR␣
activation. Subsequent studies have clarified the role of
PPAR␣ in regulating lipid metabolism and inflammation control via different pathways. In the main pathway,
PPAR␣ binds to its ligand and dimerizes with the
retinoic acid receptor (RXR). This PPAR␣–RXR heterodimer binds to DNA motifs (termed PPARresponsive elements) in the promoters of many target
genes, particularly those implicated in lipid metabolism.
Triglyceride reduction is caused by the up-regulation of
lipoprotein lipase and the enzymes involved in
␤-oxidation and down-regulation of apolipoprotein
C-III (21,22).
In another pathway, PPAR␣ exerts antiinflammatory activities by interfering with transcription factors, such as nuclear factor ␬B (NF-␬B) and activator
protein 1 (15,23). NF-␬B is known to be an important
redox-sensitive transcription factor that regulates the
transcription of genes encoding inflammatory cytokines
(including TNF␣, IL-1, and IL-6), adhesion molecules,
and chemokines (24,25). Fenofibrate may reduce inflammatory mediators that stimulate SAA production by
negatively regulating NF-␬B signaling pathways. In this
study, a sufficient reduction of triglyceride levels was
observed in mice that received even 0.05% fenofibrate
(Table 3), while a reduction in the SAA concentration
(Figure 3) and inhibition of amyloid deposition (Table 1
and Figure 2) continued at higher doses of fenofibrate.
In addition, the reduction in SAA concentration and
inhibition of amyloid deposition paralleled the improvement in ascites and peritoneal adhesions. These observations are consistent with our hypothesis.
In this study, we failed to show a significant
correlation between IL-6 and SAA concentrations. This
may be due to the differences in kinetics between IL-6
and SAA in the circulation, especially in the acute
inflammatory condition. In fact, other investigators have
also found that the plasma SAA concentration was not
always correlated with the IL-6 concentration in vivo
Although fenofibrate has a striking preventive
effect on reactive amyloidosis in this mouse model, its
clinical efficacy in humans with reactive amyloidosis
remains to be determined. Currently, the best way to
prevent or delay progressive AA amyloid deposition is to
reduce SAA concentrations by decreasing inflammatory
activity. In a study of patients with systemic AA amyloidosis, not only was the prevention of further accumulation
noted, but regression of the amyloid deposits was also
observed in the group with low SAA concentrations (28).
Moreover, in this group, even amyloid-related organ
dysfunction and long-term survival were improved (28).
Fenofibrate has been used safely for more than 25 years
in patients with hyperlipidemia (29,30). In humans,
PPAR␣ activation by fibrates does not cause the peroxisome proliferation–related changes in the liver that
result in hepatomegaly and liver cancer in rodents
(31,32). Therefore, an examination of the effects of
fenofibrate on reactive AA amyloidosis in humans with
RA is worthwhile.
In conclusion, fenofibrate inhibits reactive AA
amyloidosis by reducing SAA concentrations in an in-
flammatory murine model. The results of this study give
further credence to the antiinflammatory action of fenofibrate.
We thank Drs. Taisi Ogawa and Masahiko Nakano
(Mitsubishi Gas Chemical Company, Inc., Tokyo, Japan) for
their technical support. We also thank Kaken Pharmaceutical
Company, Ltd. and its research laboratory (Shizuoka, Japan)
for their kind cooperation in this study.
1. Toyoshima H, Kusaba T, Yamaguchi M. [Cause of death in
autopsied RA patients.] Ryumachi 1993;33:209–14. Japanese.
2. Kobayashi H, Tada S, Fuchigami T, Okuda Y, Takasugi K,
Matsumoto T, et al. Secondary amyloidosis in patients with
rheumatoid arthritis: diagnostic and prognostic value of gastroduodenal biopsy. Br J Rheumatol 1996;35:44–9.
3. Nakano M, Ueno M, Nishi S, Shimada H, Hasegawa H, Watanabe
T, et al. Analysis of renal pathology and drug history in 158
Japanese patients with rheumatoid arthritis. Clin Nephrol 1998;
4. Husby G, Marhaug G, Dowton B, Sletten K, Sipe JD. Serum
amyloid A (SAA): biochemistry, genetics and the pathogenesis of
AA amyloidosis. Amyloid 1994;1:119–37.
5. Yamada T. Serum amyloid A (SAA): a concise review of biology,
assay methods and clinical usefulness. Clin Chem Lab Med
6. Jensen LE, Whistehead AS. Regulation of serum amyloid A
expression during the acute-phase response. Biochem J 1988;334:
7. Benditt EP, Eriksen N. Amyloid protein SAA is associated with
high density lipoprotein from human serum. Proc Natl Acad Sci
U S A 1977;74:4025–8.
8. Nakai H, Ozaki S, Kano S, Goto M, Komatsubara Y, Kondo S, et
al. [Clinical characteristics and genetic background of secondary
amyloidosis associated with rheumatoid arthritis in Japanese.]
Ryumachi 1996;36:25–33. Japanese.
9. Okuda Y, Yamada T, Takasugi K, Takeda M, Nanba S, Onishi M,
et al. [Serum amyloid A (SAA) 1, SAA 2 and apolipoprotein E
isotype frequencies in rheumatoid arthritis patients with AA
amyloidosis.] Ryumachi 1999;39:3–10. Japanese.
10. Fuks A, Zucker-Franklin D. Impaired Kupffer cell function precedes development of secondary amyloidosis. J Exp Med 1985;
11. Olivier P, Plancke MO, Marzin D, Clavey V, Sauzieres J, Fruchart
JC. Effects of fenofibrate, gemfibrozil nicotinic acid on plasma
lipoprotein levels in normal and hyperlipidemic mice: a proposed
model for drug screening. Atherosclerosis 1988;70:107–14.
12. Stales B, Schnoojans K, Fruchart JC, Auwerx J. The effects of
fenofibrates and thiazolidiones on plasma triglyceride metabolism
are mediated by distinct peroxisome proliferator activated receptors (PPARs). Biochimie 1997;79:95–9.
13. Pineda Torra I, Gervois P, Staels B. Peroxisome proliferatoractivated receptor alpha in metabolic disease, inflammation atherosclerosis and aging. Curr Opin Lipidol 1999;10:151–9.
14. Madej A, Okopien B, Kowalski J, Zielinski M, Wysocki J, Szygula
B, et al. Effects of fenofibrate on plasma cytokine concentrations
in patients with atherosclerosis and hyperlipoproteinemia IIb. Int
J Clin Pharmacol Ther 1998;36:345–9.
15. Staels B, Koenig W, Habib A, Merval R, Lebret M, Pineda Torra
I, et al. Activation of human aortic smooth muscle cells is inhibited
by PPAR␣ but not by PPAR␥ activators. Nature 1998;393:790–3.
16. Kockz M, Gervois PP, Poulain P, Derudas B, Peters JM, Gonzalez
FJ, et al. Fibrates suppress fibrinogen gene expression in rodents
via activation of the peroxisome proliferator-activated receptoralpha. Blood 1999;93:2991–8.
17. Tsuboyama-Kasaoka N, Takahashi M, Kim H, Ezaki O. Upregulation of liver uncoupling protein-2 mRNA by either fish oil
feeding or fibrate administration in mice. Biochem Biophys Res
Commun 1999;257:879–85.
18. Johan K, Westermark G, Engstrom U, Gustavsson A, Hultman P,
Westermark P. Acceleration of amyloid protein A amyloidosis by
amyloid-like synthetic fibrils. Proc Natl Acad Sci U S A 1998;95:
19. Axelrad M, Kisilevsky R, Willmer J, Chen SJ, Skinner M. Further
characterization of amyloid-enhancing factor. Lab Invest 1982;47:
20. Issemann I, Green S. Activation of a member of the steroid
hormone receptor superfamily that is activated by a peroxisome
proliferator. Nature 1990;347:645–50.
21. Schmidt A, Endo N, Rutledge SJ, Vogel R, Shinar D, Rodan GA.
Identification of a new member of the steroid hormone receptor
superfamily that is activated by a peroxisome proliferator and fatty
acids. Mol Endocrinol 1992;6:1634–41.
22. Schoonjans K, Staels B, Auwerx J. Role of the peroxisome
proliferator-activated receptor (PPAR) in mediating the effects of
fibrates and fatty acids on gene expression. J Lipid Res 1996;37:
23. Delerive P, De Bosscher K, Besnard S, Berghe WV, Peters JM,
Gonzalez FJ, et al. Peroxisome proliferator-activated receptor ␣
negatively regulates the vascular inflammatory gene response by
negative cross-talk with transcription factors NF-␬B and AP-1.
J Biol Chem 1999;274:32048–54.
24. Baeuerle PA. The inducible transcription activator NF-kappa B:
regulation by distinct protein subunits. Biochim Biophys Acta
Tomita N, Morishita R, Tomita S, Gibbons GH, Zhang L,
Horiuchi M, et al. Transcription factor decoy for NF kappa B
inhibits TNF-alpha-induced cytokine and adhesion molecule expression in vivo. Gene Ther 2000;7:1326–32.
Van Leeuwen MA, Westra J, Limburg PC, van Riel PL, van
Rijswijk MH. Clinical significance of interleukin-6 measurement in
early rheumatoid arthritis: relation with laboratory and clinical
variables and radiological progression in a three year prospective
study. Ann Rheum Dis 1995;54:674–7.
Hsu HC, Zhou T, Yang PA, Herrera GA, Mountz JD. Increased
acute-phase response and renal amyloidosis in aged CD2-fastransgenic mice. J Immunol 1997;158:5988–96.
Gillmore JD, Lovat LB, Persey MR, Pepys MB, Hawkins PN.
Amyloid load and clinical outcome in AA amyloidosis in relation
to circulating concentration of serum amyloid A protein. Lancet
Krempf M, Rohmer V, Farnier M, Issa-Sayegh M, Corda C,
Sirugue I, et al. Efficacy and safety of micronised fenofibrate in a
randomised double-blind study comparing four doses from 200 mg
to 400 mg daily with placebo in patients with hypercholesterolemia. Diabetes Metab 2000;26:184–91.
Rabasa-Lhoret R, Rasamisoa M, Avignon A, Monnier L. Rare
side-effects of fenofibrate. Diabetes Metab 2001;27:66–8.
Holden PR, Tugwood JD. Peroxisome proliferator-activated receptor alpha: role in rodent liver cancer and species differences. J
Mol Endocrinol 1999;22:1–8.
Peters J, Cattley RC, Gonzalez FJ. Role of PPAR alpha in the
mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator Wy-14643. Carcinogenesis 1997;18:2029–33.
Без категории
Размер файла
1 061 Кб
inhibits, mice, fenofibrate, amyloidosis, reactive
Пожаловаться на содержимое документа